Process for preparing tapinarof

ABSTRACT

The present invention provides processes for the preparation of 3, 5-Dihydroxy-4-isopropyl-trans-stilbene or a salt or solvate thereof and novel intermediates used therein. In some embodiments the 3, 5-Dihydroxy-4-isopropyl-trans-stilbene is prepared from (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione. Also disclosed are crystal forms of 3, 5-Dihydroxy-4-isopropyl-trans-stilbene or a salt or solvate thereof and pharmaceutical compositions comprising same.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims benefit of and priority to U.S.Provisional No. 62/584,192 entitled “PROCESS,” filed Nov. 10, 2017, thecontents of which is hereby incorporated by reference in its entirety.

SUMMARY OF THE INVENTION

Some embodiments of the present invention provides a processes for thepreparation of the compound of Formula (I) or a salt thereof and tonovel intermediates used therein

Some embodiments of the present invention describe a compound of Formula(IIa) or a salt thereof

and processes for preparing same.

Some embodiments of the present invention describe a compound of Formula(IVa) or a salt thereof

and processes for preparing same.

Some embodiments of the present invention describe a compound of Formula(V) or a salt thereof

and processes for preparing same.

Some embodiments of the present invention describe a compound of Formula(VI) or a salt thereof

and processes for preparing same.

Some embodiments of the present invention describe a pharmaceuticalcomposition which comprises a compound of Formula (I) or a salt orsolvate thereof prepared according to the processes of the presentinvention and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of the compoundof Formula (I) in crystalline solid state form (Form 1).

FIG. 2 shows an X-ray powder diffraction (XRPD) pattern of an aceticacid solvate of the compound of Formula (I) in crystalline solid stateform.

DETAILED DESCRIPTION OF THE INVENTION

3, 5-Dihydroxy-4-isopropyl-trans-stilbene, also known as(E)-2-isopropyl-5-styrylbenzene-1,3-diol or tapinarof, of Formula (I) isa natural product derived from bacteria

This compound has several potentially useful biological responsesincluding antibacterial, antioxidant and anti-cancer activity. PCTpatent application WO200142231 discloses polyhydroxystilbenes andstilbene oxides as antipsoriatic agents and protein kinase inhibitors.

Several routes to the synthesis of the compound of Formula (I) are knownin the art. Chinese patent application CN101648851 describes a route ofsynthesis via the formation of the (E)-olefin viaHorner-Wadsworth-Emmons olefination. Routes are also known which are viathe introduction of the isopropyl group onto a substituted resorcinolderivative via Friedel-Crafts alkylation.

An alternative synthetic approach, similar to known biosynthesis route,was described by Kronenwerth et al. (Eur. J. Org. Chem. 2014,8026-8028). In this route, however, there are problems throughout thesynthesis with low yields of the intermediates and the final product.There is also a toxicity problem associated with incomplete removal oftrace amounts of mercury in isopropylstilbene which makes this routeunsuitable for large scale manufacturing of a pharmaceutical product.

Schamp et al. (Tetrahedron, 1973, 29, 3857-3859) discloses a synthesisof simple 2-substituted resorcinols such as 2-methyl-, 2-benzyl- and2-acetylresourcinol from the corresponding 1,3-cyclohexanediones. Thereported conditions involve the chlorination of the1,3-cyclohexanediones followed by elimination of HCl upon heating with a25% solution of dry hydrogen chloride in dimethylformamide.

There exists a need for an efficient and scalable route for the largescale manufacturing of the compound of Formula (I), in particular a highyielding synthesis with no potential toxicity problems.

The present invention provides a number of embodiments relating to aprocess which is summarised in Scheme 1 below:

Preparation of the Compound of Formula (I)-Process A

Some embodiments describe a process for the preparation of a compound ofFormula (I) or a salt or solvate thereof

comprising one or more of the process steps (a), (b) and (c) wherein:

(a) comprises reaction of a compound of Formula (III) or a salt thereof

to form a compound of Formula (II) or a salt thereof

wherein X is Cl, Br, or I, and thereafter (ii) conversion of thecompound of Formula (II) or a salt thereof into the compound of Formula(I) or a salt or solvate thereof;

(b) comprises conversion of a compound of Formula (VI) or a salt thereof

into a compound of Formula (III) or a salt thereof

and thereafter conversion of the compound of Formula (III) or a saltthereof into a compound of Formula (I) or a salt or solvate thereof; and

(c) comprises conversion of a compound of Formula (IX) or a salt thereof

into a compound of Formula (VI) or a salt thereof

and thereafter conversion of the compound of Formula (VI) or a saltthereof into a compound of Formula (I) or a salt or solvate thereof.

Some embodiments describe processes for making compounds of Formula (I)or a salt or solvate thereof comprising at least one of process steps(a) to (c). The processes of the present invention may include one, twoor all three of process steps (a), (b) and (c).

The product of each of process steps (a), (b) and (c) may optionally becrystallised.

In some embodiments the compound of Formula (I) prepared by process (a),(b) or (c) is in crystalline solid state form. In one embodiment, thereis provided, the compound of Formula (I) in crystalline solid state form(Form 1) which has an X-ray powder diffraction pattern substantially asshown in FIG. 1. In another embodiment there is provided the compound ofFormula (I) in crystalline solid state characterised by an X-ray powderdiffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1,20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 20experimental error). In another embodiment there is provided thecompound of Formula (I) in crystalline solid state characterised by anX-ray powder diffraction (XRPD) pattern with at least nine, or at leasteight, or at least seven, or at least six, or at least five, or at leastfour, or at least three specific peaks selected from 15.0, 17.8, 19.1,20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 20experimental error).

Process Step (a)

In some embodiments X is Cl.

In some embodiments wherein X is Cl, the reaction is carried out using achlorination reagent selected from the group consisting of1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS)and trichloroisocyanuric acid (TCCA).

In some embodiments the chlorination reagent is DCDMH.

In some embodiments the conversion of the compound of Formula (II) or asalt thereof to a compound of Formula (I) or a salt thereof is carriedout in a suitable solvent and optionally with an additive material.

It was found that such a conversion was achieved in good yields with anumber of solvents. In some embodiments the conversion of the compoundof Formula (II) or a salt thereof to give a compound of Formula (I) or asalt thereof is carried out in a suitable solvent which is a polaraprotic solvent selected from the group consisting of dimethylformamide(DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),dimethylacetamide (DMAC) and sulfolane.

Whilst the use of a solvent such as DMF was operationally simple, theuse of such in the manufacture of a pharmaceutical product is a matterof potential concern due to its reproductive toxicity. An alternativesolvent was therefore sought that would be suitable for use in the largescale manufacture of a pharmaceutical product.

It was found, however, that the conversion of the compound of Formula(II) or a salt thereof, e.g. wherein X is Cl, to a compound of Formula(I) or a salt thereof did not progress well for alternative solvents,including some commonly used solvents. In such circumstances it wasfound that use of an additive material, such as benzylethylammoniumchloride, facilitated this reaction in good yields. This is demonstratedin Table 1 below.

TABLE 1

Yield without Yield with Solvent additive additive^(2,3) Acetonitrile Noproduct 96% Toluene No product 98% 2-Me-THF No product 95% i-PrOAc <5%93% ¹Reaction were carried out in sealed tubes which allowed for heatingwell above the boiling point of the solvent. ²Additive = 2 equivalentsof benzyltriethylammonium chloride. ³Yields based on HPLC assay of crudereaction mixture.

A further investigation was therefore carried out into the use of arange of different additive materials in the conversion of the compoundof Formula (II) or a salt thereof, in which X is Cl, to a compound ofFormula (I) or a salt or solvate thereof. These results are representedin Table 2 below.

TABLE 2

Additive Time Yield¹ BnEt₃Cl 4 hours 96% Bu₄NCl 4 hours 93% Et₄NCl 4hours 99% Me₄NCl Overnight 90% cysteine•HCl Overnight 8% NH₄Cl OvernightTrace imidazole•HCl 5 hours 20% Et₃N•HCl Overnight 88% Conc. HCl 5 hours31% NaCl Overnight Trace LiCl Overnight 20% ¹Yields based on HPLC assayof crude reaction mixture.

In some embodiments the conversion of the compound of Formula (II) or asalt thereof to a compound of Formula (I) or a salt thereof is carriedout in the presence of an additive reagent which is a quaternaryammonium salt, for example a quaternary ammonium bromide salt or aquaternary ammonium chloride salt. In some embodiments the quaternaryammonium bromide salt is tetrabutylammonium bromide. In some embodimentsthe quaternary ammonium chloride salt is selected from the groupconsisting of benzyltriethylammonium chloride, tetrabutylammoniumchloride, tetraethylammonium chloride and tetramethylammonium chloride.In some embodiments the quaternary ammonium chloride salt istetraethylammonium chloride.

In some embodiments the conversion of the compound of Formula (II) or asalt thereof to give a compound of Formula (I) or a salt or a solvatethereof in the presence of an additive reagent is carried out in asolvent selected from the group consisting of acetonitrile, toluene,2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutylketone. It was found that acetonitrile provided the best combination ofsolubility and high boiling point. In some embodiments this conversionis carried out in a solvent which is acetonitrile.

Embodiments of the present disclosure describe a compound of Formula(IIa) or a salt thereof

The compound of Formula (I) may be prepared in the form of an aceticacid solvate thereof. Some embodiments of the present disclosuredescribe a compound of Formula (I) in the form of an acetic acid solvatethereof. It has been found that formation of the acetic acid solvate ofthe compound of Formula (I) provides impurity and colour purgingcapabilities to the process of the invention. The acetic acid solvate ofthe compound of Formula (I) can thereafter be converted into thecompound of Formula (I).

In some embodiments there is provided an acetic acid solvate of thecompound of Formula (I) in crystalline solid state form. In someembodiments, there is provided, an acetic acid solvate of the compoundof Formula (I) in crystalline solid state form which has an X-ray powderdiffraction pattern substantially as shown in FIG. 2. In anotherembodiment there is provided an acetic acid solvate of the compound ofFormula (I) in crystalline solid state characterised by an X-ray powderdiffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4,16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimentalerror). In another embodiment there is provided an acetic acid solvateof the compound of Formula (I) in crystalline solid state characterisedby an X-ray powder diffraction (XRPD) pattern with at least six, or atleast five, or at least four, or at least three specific peaks selectedfrom peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all2θ values, ±0.1° 2θ experimental error).

In some embodiments the process further comprises a step ofrecrystallization of the compound of Formula (I) or a salt or solvatethereof. In some embodiments recrystallization is carried out usingmethanol and water.

Process Step (b)

In some embodiments conversion of a compound of Formula (VI) or a saltthereof into a compound of Formula (III) or a salt thereof comprises adecarboxylation of the compound of Formula (VI) or a salt thereof toform the compound of Formula (V) or a salt thereof

followed by esterification of the compound of Formula (V) or a saltthereof to form the compound of Formula (IV) or a salt thereof

wherein R is C₁₋₄ alkyl; and thereafter cyclization of the compound ofFormula (IV) or a salt thereof to form the compound of Formula (III) ora salt thereof.

In some embodiments conversion of a compound of Formula (VI) or a saltthereof into a compound of Formula (V) or a salt thereof comprisesdecarboxylation in the presence of a base. In some embodiments the baseis selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In a particular embodiments the base istriethylamine.

In some embodiments R is methyl, ethyl, propyl, or butyl. In someembodiments R is t-butyl. In some embodiments R is methyl.

In some embodiments esterification of a compound of Formula (V) or asalt thereof to a compound of Formula (IV) or a salt thereof isperformed using methanol, for example esterification is performed usingmethanol and hydrochloric acid.

In some embodiments cyclization of a compound of Formula (IV) or a saltthereof to a compound of Formula (III) or a salt thereof is performedusing potassium tert-butoxide.

In some embodiments the compound of Formula (III) or a salt thereof isacidified and isolated by precipitation with methylcyclohexane.

In some embodiments the conversion of a compound of Formula (VI) or asalt thereof into a compound of Formula (III) or a salt thereof istelescoped such that the compounds of Formula (V) or a salt thereof andFormula (IV) or a salt thereof are not isolated.

Some embodiments describe a compound of Formula (IVa) or a salt thereof

The compound of Formula (IVa), namely (E)-methyl7-methyl-5-oxo-3-styryloctanoate, is characterized by the followingdata.

¹H NMR (500 MHz, DMSO) δ 7.33 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 6.37(d, 1H, J=16.0 Hz), 6.15 (dd, 1H, J=8.1 Hz, J=16.0 Hz), 3.56 (s, 3H),3.09 (m, 1H), 2.60 (m, 2H), 2.50 (dd, 1H, 6.1 Hz, J=15.4 Hz), 2.42 (dd,1H, J=8.1 Hz, J=15.4 Hz), 2.29 (d, 2H, 7.0 Hz), 2.00 (m, 1H), 0.82 (s,6H, 6.7 Hz).

¹³C NMR (125 MHz, DMSO) δ 208.7 (C), 171.8 (C), 136.8 (C), 131.9 (CH),129.5 (CH), 128.5 (CH), 127.2 (CH), 125.9 (CH), 51.4 (CH₂), 51.2 (CH₃),46.7 (CH₂), 38.5 (CH₂), 34.4 (CH), 23.8 (CH), 22.29 (CH₃), 22.26 (CH₃).

HRMS-APCI (m/z) [M+H]⁺ calculated for C₁₈H₂₅O₃, 289.1798; found,289.1719.

In a some embodiments there is provided a compound of Formula (V) or asalt thereof

The compound of Formula (V), namely (E)-7-methyl-5-oxo-3-styryloctanoicacid, is characterized by the following data.

¹H NMR (700 MHz, DMSO) δ 12.13 (s, 1H), 7.33 (m, 2H), 7.29 (m, 2H), 7.20(m, 1H), 6.37 (d, 1H, J=16 Hz), 6.17 (dd, 1H, J=8.0 Hz, J=16.0 Hz), 3.07(m, 1H), 2.60 (m, 2H), 2.46 (dd, 1H, J=6.2 Hz, J=15.5 Hz), 2.33 (dd, 1H,J=8.0, J=15.5 Hz), 2.30 (d, 2H, J=7.1 Hz), 2.0 (m, 1H), 0.82 (d, 6H,J=6.6 Hz).

¹³C NMR (176 MH, DMSO) δ 208.8 (C), 172.9 (C), 136.9 (C), 132.2 (CH),129.3 (CH), 128.5 (CH), 127.1 (CH), 125.9 (CH), 51.4 (CH₂), 46.8 (CH₂),38.9 (CH₂), 34.4 (CH), 23.8 (CH), 22.3 (CH₃), 22.3 (CH₃).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₁₇H₂₃O₃, 275.1642; found, 275.1635.

In some embodiments there is provided a compound of Formula (VI) or asalt thereof.

The compound of Formula (III) or a salt thereof may be converted into acompound of Formula (I) or a salt or solvate thereof by methodsdescribed herein (e.g. process step (a)) or by methods known to theperson skilled in the art (e.g. by methods described in Kronenwerth, M.et al.). In some embodiments the compound of Formula (III) or a saltthereof may be converted into a compound of Formula (I) or a salt orsolvate thereof by process step (a).

Process Step (c)

In some embodiments conversion of a compound of Formula (IX) or a saltthereof into a compound of Formula (VI) or a salt thereof comprises thecondensation of the compound of Formula (IX) or a salt thereof withmethyl isobutyl ketone to form the compound of Formula (VIII) or a saltthereof

followed by addition of a malonic ester (R₁O(O)C—CH₂—C(O)OR₂) to form acompound of Formula (VII) or a salt thereof

wherein R₁ and R₂ are independently C₁₋₄ alkyl;and thereafter hydrolysation of the compound of Formula (VII) or a saltthereof to form the compound of Formula (VI) or a salt thereof.

In some embodiments condensation of a compound of Formula (IX) or a saltthereof into a compound of Formula (VIII) or a salt thereof is performedusing lithium, potassium or sodium hydroxide, for example thecondensation is performed using potassium or sodium hydroxide inmethanol.

In some embodiments the conversion of a compound of Formula (VIII) or asalt thereof into a compound of Formula (VII) or a salt thereofcomprises the addition of a malonic ester which is di-tert-butylmalonate or diethyl malonate.

In some embodiments the conversion of a compound of Formula (IX) or asalt thereof into a compound of Formula (VI) or a salt thereof istelescoped such that the compounds of Formula (VII) and Formula (VIII)or salts thereof are not isolated.

In some embodiments there is provided a compound of Formula (VIIa) or asalt thereof.

The compound of Formula (VIIa), namely (E)-diethyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate, is characterized bythe following data.

¹H NMR (700 MHz, DMSO) δ 7.30 (m, 2H), 7.30 (m, SH0, 7.21 (m, 1H), 6.39(d, 1H) J=15.8 Hz), 6.14 (dd, 1H, J=15.99 Hz, J=8.9 Hz), 4.12 (q, 2H,J=7.13 Hz), 4.06 (m, 2H), 3.68 (d, 1H, J=8.1 Hz), 3.33 (m, 1H), 2.73(dd, 1H, J=16.9 Hz, J=9.0 Hz), 2.63 (m, 1H,), 2.28 (d, 2H, 6.9 Hz), 1.98(m, 1H, 6.7 Hz), 1.16 (t, 3H, J=7.1 Hz), 1.10 (t, 3H, J=7.0 Hz), 0.81(d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.7 Hz).

¹³C NMR (176 MHz, DMSO) δ 208.1 (C), 167.7 (C), 167.6 (C), 136.6 (C),131.4 (CH), 128.9 (CH), 127.4 (CH), 125.9 (CH), 61.0 (CH2), 60.8 (CH2),55.0 (CH), 51.3 (CH2), 44.8 (CH2), 37.7 (CH), 23.8 (CH), 22.3 (CH3),22.2 (CH3), 13.9 (CH3), 13.9 (CH3).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₂₂H₃₁O₅, 375.2166; found, 375.2158.

The compound of Formula (VI) or a salt thereof may be converted into acompound of Formula (I) or a salt or solvate thereof by methodsdescribed herein (e.g. process steps (a) and (b)) or by methods known tothe person skilled in the art (e.g. by methods described in Kronenwerth,M. et al.). In some embodiments the compound of Formula (VI) or a saltthereof may be converted into a compound of Formula (I) or a salt orsolvate thereof by process steps (a) and (b).

Preparation of the Compound of Formula (I)-Process B

Some embodiments herein describe a process for preparing a compound ofFormula (I) or salt or solvate thereof

comprising aromatizing a compound of Formula (II) or salt thereof

wherein X is Cl, Br, or I; to obtain the compound of Formula (I). Insome embodiments the process further comprises purifying the compound ofFormula (I) or a salt or solvate thereof. In some embodiments thepurifying comprises crystallization of the compound of Formula (I) or asalt or solvate thereof. In some embodiments the compound of Formula (I)is a crystal form described in any embodiment described herein. In someembodiments the compound of Formula (I) is crystal form 1. In someembodiments the compound of Formula (I) is an anhydrous crystal. In someembodiments the compound of Formula (I) has an X-ray powder diffractionpattern substantially as shown in FIG. 1. In some embodiments thecompound of Formula (I) is in a crystalline solid state characterised byan X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0,17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (allvalues ±0.1° 20 experimental error). In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with at least nine, or at least eight,or at least seven, or at least six, or at least five, or at least four,or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2,21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isan acetic acid solvate in crystalline solid state form. In someembodiments, the compound of Formula (I) is an acetic acid solvate incrystalline solid state form which has an X-ray powder diffractionpattern substantially as shown in FIG. 2. In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 2θ values, ±0.1° 2θ experimental error). In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withat least six, or at least five, or at least four, or at least threespecific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error). In someembodiments X is Cl. In some embodiments the aromatizing is carried outin a suitable solvent and optionally with an additive reagent. In someembodiments the aromatizing is carried out in a suitable solvent whichis a polar aprotic solvent selected from the group consisting ofdimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodimentsthe aromatizing is carried out in the presence of an additive reagent ina solvent selected from the group consisting of acetonitrile, toluene,2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutylketone. In some embodiments the aromatizing is carried out inacetonitrile in the presence of an additive reagent. In some embodimentsthe additive reagent is a quaternary ammonium salt. In some embodimentsthe quaternary ammonium salt is selected from the group consisting oftetrabutylammonium bromide, benzyltriethylammonium chloride,tetrabutylammonium chloride, tetraethylammonium chloride andtetramethylammonium chloride. In some embodiments the quaternaryammonium salt is tetraethylammonium chloride. In some embodiments thearomatizing is carried out in acetonitrile with tetraetylammoniumchloride.

In some embodiments the process further comprises halogenating acompound of Formula (III) or salt thereof

with a halogenating agent to obtain the compound of Formula (II) or asalt thereof. In some embodiments the halogenating agent is selectedfrom 1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide(NCS); and trichloroisocyanuric acid (TCCA). In some embodiments thehalogenating agent is DCDMH and the compound of Formula (II) or a saltthereof is a compound of Formula (IIa) or a salt thereof:

In some embodiments the halogenating is carried out in methanol. In someembodiments the halogenation agent is DCDMH and the halogenation iscarried out in methanol.

In some embodiments the process further comprises cyclizing a compoundof Formula (IV) or salt thereof

wherein R is C₁₋₄ alkyl, to obtain the compound of Formula (III) or asalt thereof. In some embodiments R is selected from the groupconsisting of methyl, ethyl, propyl, or butyl. In some embodiments R ist-butyl. In some embodiments R is methyl. In some embodiments thecyclization comprises contacting the compound of Formula (IV) or a saltthereof, with a base. In some embodiments the cyclization is performedusing potassium tert-butoxide. In some embodiments the cyclization iscarried out in 2-methyltetrahydrofuran. In some embodiments thecyclization comprises treating a compound of Formula (IV) or a saltthereof, for example a compound of (IVa) or a salt thereof, withpotassium tert-butoxide in 2-methyltetrahydrofuran. In some embodimentsthe compound of Formula (III) or a salt thereof is further acidified andisolated by precipitation with methylcyclohexane.

In some embodiments the process further comprises esterifying a compoundof Formula (V) or salt thereof

to obtain the compound of Formula (IV) or a salt thereof. In someembodiments the esterifying is carried out using methanol andhydrochloric acid to obtain compound (IV). In some embodiments theesterifying comprises treating the compound of Formula (V) or a saltthereof with aqueous hydrochloric acid in methanol.

In some embodiments the process further comprising decarboxylating acompound of Formula (VI) or a salt thereof

to obtain the compound of Formula (V) or a salt thereof. In someembodiments the decarboxylating comprises the presence of a base. Insome embodiments the base is selected from imidazole, pyridine, andlutidine (2,6-dimethylpyridine). In some embodiments the base istrimethylamine. In some embodiments the decarboxylating comprisesheating the compound of Formula (VI) or a salt thereof in the presenceof trimethylamine.

In some embodiments the process further comprises hydrolyzing a compoundof Formula (VII) or a salt thereof

wherein each R₁ and R₂ is independently C₁₋₄ alkyl; to obtain thecompound of Formula (VI) or a salt thereof. In some embodiments each ofR₁ and R₂ is ethyl (VIIa). In some embodiments the hydrolyzing comprisestreating the compound of Formula (VII) or a salt thereof, with sodiumhydroxide. In some embodiments the hydrolyzing comprises treating thecompound of Formula (VII) or a salt thereof with sodium hydroxide inethanol. In some embodiments the process comprises hydrolyzing acompound of Formula (VIIa) or a salt thereof comprising treating thecompound of Formula (VIIa) or a salt thereof with sodium hydroxide inethanol.

In some embodiments the process further comprises adding a dialkylmalonic ester (R₁O(O)C—CH₂—C(O)OR₂ wherein each R₁ and R₂ isindependently C₁₋₄ alkyl), to a compound of Formula (VIII) or a saltthereof

to obtain the compound of Formula (VII) or a salt thereof. In someembodiments the dialkyl malonic ester is di-tert-butylmalonate ordiethyl malonate. In some embodiments, the adding comprises contactingthe dialkyl malonic ester with the compound of Formula (VIII) or a saltthereof in the presence of lithium bromide/triethylamine.

In some embodiments, the process further comprises condensingtrans-cinnamaldehyde (compound of Formula (IX)) or a salt thereof

with methyl isobutyl ketone to form the compound of Formula (VIII) or asalt thereof. In some embodiments the condensing comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of sodium hydroxide in methanol.Preparation of the Compound of Formula (I)-Process C

In some embodiments described herein is a process for preparing acompound of Formula (I) or a salt or solvate thereof

comprising:

-   -   a) decarboxylating a compound of Formula (VI) or a salt thereof

-   -   to form a compound of Formula (V) or a salt thereof

-   -   b) esterifying the compound of Formula (V) or a salt thereof to        form a compound of Formula (IV) or a salt thereof

wherein R is C₁₋₄ alkyl;

-   -   c) cyclizing the compound of Formula (IV) or a salt thereof to        form a compound of Formula (III) or a salt thereof,

-   -   d) halogenating the compound of Formula (III) or a salt thereof        to form a compound of Formula (II) or a salt thereof,

-   -   wherein X is selected from Br, Cl and I; and    -   e) aromatizing the compound of Formula (II) or a salt thereof to        form the compound of Formula (I) or a salt or solvate thereof.

In some embodiments the process further comprises isolating the compoundof Formula (III) or a salt thereof in step c). In some embodiments theprocess comprises isolating the compound of Formula (II) or a saltthereof in step d). In some embodiments the process further comprisespurifying the compound of Formula (I) or a salt or solvate thereofobtained from step e). In some embodiments the purifying comprisescrystallization of the compound of Formula (I) or a salt or solvatethereof. In some embodiments the compound of Formula (I) is a crystalform described in any embodiment described herein. In some embodimentsthe compound of Formula (I) is crystal form 1. In some embodiments thecompound of Formula (I) is an anhydrous crystal. In some embodiments thecompound of Formula (I) has an X-ray powder diffraction patternsubstantially as shown in FIG. 1. In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8,19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values±0.1° 2θ experimental error). In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with at least nine, or at least eight,or at least seven, or at least six, or at least five, or at least four,or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2,21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isan acetic acid solvate in crystalline solid state form. In someembodiments, the compound of Formula (I) is an acetic acid solvate incrystalline solid state form which has an X-ray powder diffractionpattern substantially as shown in FIG. 2. In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 2θ values, ±0.1° 2θ experimental error). In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withat least six, or at least five, or at least four, or at least threespecific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees (all 20 values, ±0.1° 2θ experimental error).

In some embodiments the decarboxylating of a compound of Formula (VI) ora salt thereof in step a) comprises the presence of a base. In someembodiments the base is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base is trimethylamine.In some embodiments the decarboxylating comprises heating the compoundof Formula (VI) or a salt thereof in the presence of trimethylamine.

In some embodiments R of the compound of Formula (IV) or a salt thereofin step b) is selected from the group consisting of methyl, ethyl,propyl, or butyl. In some embodiments R of the compound of Formula (IV)or a salt thereof in step b) is t-butyl. In some embodiments R of thecompound of Formula (IV) or a salt thereof in step b) is methyl. In someembodiments the esterifying of the compound of Formula (V) or a saltthereof in step b) is carried out using methanol and hydrochloric acidto obtain compound (IV) or a salt or solvate thereof. In someembodiments the esterifying comprises treating the compound of Formula(V) or a salt thereof with aqueous hydrochloric acid in methanol.

In some embodiments the cyclization in step c) comprises contacting thecompound of Formula (IV) or salt thereof with a base. In someembodiments the cyclization is performed using potassium tert-butoxide.In some embodiments the cyclization is carried out in2-methyltetrahydrofuran. In some embodiments the cyclization comprisestreating a compound of Formula (IV) or a salt thereof, for example acompound of (IVa) or a salt thereof, with potassium tert-butoxide in2-methyltetrahydrofuran. In some embodiments the compound of Formula(III) or a salt thereof is further acidified and isolated byprecipitation with methylcyclohexane.

In some embodiments X of the compound of Formula (II) or a salt thereofin step d) is Cl, Br, or I. In some embodiments X of the compound ofFormula (II) or a salt thereof in step d) is Cl. In some embodiments thehalogenating comprises treating the compound of Formula (III) or a saltthereof with a halogenating agent. In some embodiments the halogenatingagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH);N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In someembodiments the halogenating agent is DCDMH and the compound of Formula(II) or a salt thereof is a compound of Formula (IIa) or a salt thereof.

In some embodiments the aromatizing in step e) is carried out in asuitable solvent and optionally with an additive reagent. In someembodiments the aromatizing in step e) is carried out in a suitablesolvent which is a polar aprotic solvent selected from the groupconsisting of dimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodimentsthe aromatizing in step e) is carried out in the presence of an additivereagent in a solvent selected from the group consisting of acetonitrile,toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methylisobutyl ketone. In some embodiments the aromatizing is carried out inacetonitrile in the presence of an additive reagent. In some embodimentsthe additive reagent is a quaternary ammonium salt. In some embodimentsthe quaternary ammonium salt is selected from the group consisting oftetrabutylammonium bromide, benzyltriethylammonium chloride,tetrabutylammonium chloride, tetraethylammonium chloride andtetramethylammonium chloride. In some embodiments the quaternaryammonium salt is tetraethylammonium chloride. In some embodiments thearomatizing is carried out in acetonitrile with tetraetylammoniumchloride.

In some embodiments R of step b) is methyl and X of step d) is chloro.

In some embodiments the compound of Formula (VI) or a salt thereof instep a) is prepared by a process comprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding a dialkyl malonic ester of the Formula        R₁O(O)C—CH₂—C(O)OR₂, wherein each of R₁ and R₂ is independently        C₁₋₄ alkyl, to the compound of Formula (VIII) or a salt thereof        to form a compound of Formula (VII) or a salt thereof

-   -   wherein each R₁ and R₂ are as defined for the dialkyl malonic        ester;    -   iii. hydrolyzing the compound of Formula (VII) or a salt        thereof, to form the compound of Formula (VI) or a salt thereof.

In some embodiments the condensing in step i. comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step i. comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol.

In some embodiments each of R¹ and R² in step ii. is ethyl. In someembodiments the dialkyl malonic ester in step ii. isdi-tert-butylmalonate or diethyl malonate. In some embodiments, theadding in step ii. comprises contacting the malonic ester with thecompound of Formula (VIII) or a salt thereof in the presence of lithiumbromide/triethylamine.

Preparation of the Compound of Formula (I)-Process D

Some embodiments herein describe a process for preparing the compound ofFormula (I) or a salt or solvate thereof

comprising:

-   -   a) heating a compound of Formula (VI)

-   -   -   with catalytic triethylamine to form a compound of Formula            (V)

-   -   b) heating the compound of Formula (V) with methanol and aqueous        hydrochloric acid to form a compound of Formula (IVa)

-   -   c) treating a cooled solution of the compound of Formula (IVa)        with potassium tert-butoxide to form a compound of Formula (III)

-   -   d) heating the compound of Formula (III) with 1,        3-dichloro-5,5-dimethylhydantoin to form a compound of Formula        (IIa)

and

-   -   e) heating the compound of Formula (IIa) with tetraethylammonium        chloride to form the compound of Formula (I) a salt or solvate        thereof.

In some embodiments, the process further comprises purifying thecompound of Formula (I) from step e) by crystallization. In someembodiments the process further comprises after step c), step ci)isolating the compound of Formula (III). In some embodiments the processfurther comprises after step d), step di) isolating the compound ofFormula (IIa). In some embodiments the process further comprisespurifying the compound of Formula (I) obtained from step e). In someembodiments the purifying comprises crystallization of Formula (I). Insome embodiments the compound of Formula (I) is a crystal form describedin any embodiment described herein. In some embodiments the compound ofFormula (I) is crystal form 1. In some embodiments the compound ofFormula (I) is an anhydrous crystal. In some embodiments the compound ofFormula (I) has an X-ray powder diffraction pattern substantially asshown in FIG. 1. In some embodiments the compound of Formula (I) is in acrystalline solid state characterised by an X-ray powder diffraction(XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5,22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isin a crystalline solid state characterised by an X-ray powderdiffraction (XRPD) pattern with at least nine, or at least eight, or atleast seven, or at least six, or at least five, or at least four, or atleast three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5,22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isan acetic acid solvate in crystalline solid state form. In someembodiments, the compound of Formula (I) is an acetic acid solvate incrystalline solid state form which has an X-ray powder diffractionpattern substantially as shown in FIG. 2. In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 2θ values, ±0.1° 2θ experimental error). In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withat least six, or at least five, or at least four, or at least threespecific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).

In some embodiments, the compound of Formula (VI) in step a) is preparedby a process comprising:

-   -   i. treating methyl isobutyl ketone with trans-cinnamaldehyde in        the presence of methanolic sodium hydroxide to form a compound        of Formula (VIII)

-   -   ii. treating the compound of Formula (VIII) with diethyl        malonate in the presence of lithium bromide and triethylamine to        form a compound of Formula (VIIa)

-   -   iii. hydrolyzing the compound of Formula (VIIa) with sodium        hydroxide and ethanol to obtain the compound of Formula (VI).        Preparation of the Compound of Formula (I)-Process E

Some embodiments describe a process for a particular embodiment of thepresent invention is shown in Scheme 2 below and as described in detailin the Examples.

Process for the Preparation of the Compound of Formula (VI)

Some embodiments herein describe a process for preparing a compound ofFormula (VI) or a salt thereof

comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof or a salt        thereof with methyl isobutyl ketone to form a compound of        Formula (VIII) or a salt thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine.

Process for the Preparation of the Compound of Formula (V)

Some embodiments herein describe a process for preparing a compound ofFormula (V) or a salt thereof

comprising decarboxylating a compound of Formula (VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. In some embodiments the base is selected from imidazole,pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments thebase is trimethylamine. In some embodiments the decarboxylatingcomprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine. In some embodiments the compound of Formula(VI) or a salt thereof is prepared by any process described herein. Insome embodiments the compound of Formula (VI) or a salt thereof isprepared by a process comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof.

Some embodiments herein describe a process for preparing a compound ofFormula (V) or a salt thereof

comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof

and

-   -   d) decarboxylating the compound of Formula (VI) or a salt        thereof, in the presence of a base, to form the compound of        Formula (V) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine. In some embodiments the basein step d) is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base in step d) istrimethylamine. In some embodiments the decarboxylating in step d)comprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine.

Process for the Preparation of the Compound of Formula (IVa)

Some embodiments herein describe a process for preparing a compound ofFormula (IVa) or a salt thereof

comprising esterifying a compound of Formula (V) or a salt thereof

to form the compound of Formula (IVa) or a salt thereof. In someembodiments the esterifying of the compound of Formula (V) or a saltthereof is carried out using methanol and hydrochloric acid to obtaincompound (IVa). In some embodiments the esterifying comprises treatingthe compound of Formula (V) or a salt thereof with aqueous hydrochloricacid in methanol. In some embodiments the compound of Formula (V) or asalt thereof or a salt thereof, is prepared by any method describedherein. In some embodiments the compound of Formula (V) or a saltthereof is prepared by a process comprising decarboxylating a compoundof Formula (VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. In some embodiments the compound of Formula (VI) or a saltthereof is prepared by any process described herein. In some embodimentsthe compound of Formula (VI) or a salt thereof is prepared by a processcomprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof or a salt        thereof with methyl isobutyl ketone to form a compound of        Formula (VIII) or a salt thereof

-   -   ii. adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   iii. hydrolyzing the compound of Formula (VIIa) or a salt        thereof to form the compound of Formula (VI) or a salt thereof.

Some embodiments herein describe a process for preparing a compound ofFormula (IVa) or a salt thereof

comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof

-   -   d) decarboxylating the compound of Formula (VI) or a salt        thereof, in the presence of a base, to form the compound of        Formula (V) or a salt thereof

and

-   -   e) esterifying a compound of Formula (V) or a salt thereof to        form the compound of Formula (IVa) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine. In some embodiments the basein step d) is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base in step d) istrimethylamine. In some embodiments the decarboxylating in step d)comprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine. In some embodiments the esterifying of thecompound of Formula (V) or a salt thereof in step e) is carried outusing methanol and hydrochloric acid to obtain compound (IVa). In someembodiments the esterifying in step e) comprises treating the compoundof Formula (V) or a salt thereof with aqueous hydrochloric acid inmethanol.

Process for the Preparation of the Compound of Formula (IIa)

Some embodiments herein describe a process for preparing a compound ofFormula (IIa) or a salt thereof

comprising halogenating a compound of Formula (III) or a salt thereof

to form the compound of Formula (IIa) or a salt thereof. In someembodiments the halogenating comprises treating the compound of Formula(III) or a salt thereof with a halogenating agent. In some embodimentsthe halogenating agent is selected from1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS);and trichloroisocyanuric acid (TCCA). In some embodiments thehalogenating agent is DCDMH. In some embodiments, the compound ofFormula (III) or a salt thereof is prepared by any process describedherein. In some embodiments, the compound of Formula (III) or a saltthereof is prepared by a process comprising cyclizing a compound ofFormula (IVa) or a salt thereof

to form the compound of Formula (III) or a salt thereof. In someembodiments the compound of Formula (IVa) or a salt thereof is preparedby any process described herein. In some embodiments the compound ofFormula (IVa) or a salt thereof is prepared by a process comprisingesterifying a compound of Formula (V) or a salt thereof

In some embodiments the compound of Formula (V) or a salt thereof isprepared by any process described herein. In some embodiments thecompound of Formula (V) or a salt thereof is prepared by a processcomprising decarboxylating a compound of Formula (VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. In some embodiments the compound of Formula (VI) or a saltthereof is prepared by any process described herein. In some embodimentsthe compound of Formula (VI) or a salt thereof is prepared by a processcomprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   iii. hydrolyzing the compound of Formula (VIIa) or a salt        thereof to form the compound of Formula (VI) or a salt thereof.

Some embodiments herein describe a process for preparing a compound ofFormula (IIa) or a salt thereof

comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof

-   -   d) decarboxylating the compound of Formula (VI) or a salt        thereof, in the presence of a base, to form the compound of        Formula (V) or a salt thereof

-   -   e) esterifying a compound of Formula (V) or a salt thereof to        form the compound of Formula (IVa) or a salt thereof

-   -   f) cyclizing a compound of Formula (IVa) or a salt thereof to        form the compound of Formula (III) or a salt thereof

and

-   -   g) halogenating a compound of Formula (III) or a salt thereof to        form the compound of Formula (IIa) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine. In some embodiments the basein step d) is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base in step d) istrimethylamine. In some embodiments the decarboxylating in step d)comprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine. In some embodiments the esterifying of thecompound of Formula (V) or a salt thereof in step e) is carried outusing methanol and hydrochloric acid to obtain compound (IVa). In someembodiments the esterifying in step e) comprises treating the compoundof Formula (V) or a salt thereof with aqueous hydrochloric acid inmethanol. In some embodiments the halogenating in step g) comprisestreating the compound of Formula (III) or a salt thereof with ahalogenating agent. In some embodiments the halogenating agent isselected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH);N-chlorosuccinimide (NC S); and trichloroisocyanuric acid (TCCA). Insome embodiments the halogenating agent is DCDMH.

Compound of Formula (I) Prepared by Process A

Some embodiments herein describe a compound of Formula (I) or a salt orsolvate thereof

prepared by a process comprising:a) decarboxylating a compound of Formula (VI) or a salt thereof

-   -   to form a compound of Formula (V) or a salt thereof

-   -   b) esterifying the compound of Formula (V) or a salt thereof to        form a compound of Formula (IV) or a salt thereof

wherein R is C₁₋₄ alkyl;

-   -   c) cyclizing the compound of Formula (IV) or a salt thereof to        form a compound of Formula (III) or a salt thereof

-   -   d) halogenating the compound of Formula (III) or a salt thereof        to form a compound of Formula (II) or a salt thereof

-   -   -   wherein X is selected from Br, Cl and I; and

    -   e) aromatizing the compound of Formula (II) or a salt thereof to        form the compound of Formula (I) or a salt or solvate thereof.

Some embodiments describe the compound of Formula (I) or a salt orsolvate thereof wherein the process further comprises isolating thecompound of Formula (III) or a salt thereof. Some embodiments describethe compound of Formula (I) or a salt or solvate thereof wherein theprocess comprises isolating the compound of Formula (II) or a saltthereof. Some embodiments describe the compound of Formula (I) or a saltor solvate thereof wherein the process further comprises purifying thecompound of Formula I obtained from step e). In some embodiments thepurifying comprises crystallization of Formula (I). In some embodimentsthe compound of Formula (I) is crystal form 1. In some embodiments thecompound of Formula (I) is an anhydrous crystal. In some embodiments thecompound of Formula (I) has an X-ray powder diffraction patternsubstantially as shown in FIG. 1. In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8,19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values±0.1° 2θ experimental error). In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with at least nine, or at least eight,or at least seven, or at least six, or at least five, or at least four,or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2,21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isan acetic acid solvate in crystalline solid state form. In someembodiments, the compound of Formula (I) is an acetic acid solvate incrystalline solid state form which has an X-ray powder diffractionpattern substantially as shown in FIG. 2. In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 20 values, ±0.1° 2θ experimental error). In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withat least six, or at least five, or at least four, or at least threespecific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees (all 20 values, ±0.1° 2θ experimental error).

In some embodiments the decarboxylating of the compound of Formula (VI)or a salt thereof in step a) comprises the presence of a base. In someembodiments the base is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base is trimethylamine.In some embodiments the decarboxylating comprises heating the compoundof Formula (VI) or a salt thereof in the presence of trimethylamine.

In some embodiments R of the compound of Formula (IV) or a salt thereofin step b) is selected from the group consisting of methyl, ethyl,propyl, or butyl. In some embodiments R of the compound of Formula (IV)or a salt thereof in step b) is t-butyl. In some embodiments R of thecompound of Formula (IV) or a salt thereof in step b) is methyl. In someembodiments the esterifying of the compound of Formula (V) or a saltthereof in step b) is carried out using methanol and hydrochloric acidto obtain compound (IV). In some embodiments the esterifying comprisestreating the compound of Formula (V) or a salt thereof with aqueoushydrochloric acid in methanol.

In some embodiments the cyclization in step c) comprises contacting thecompound of Formula (IV) or salt thereof, with a base. In someembodiments the cyclization is performed using potassium tert-butoxide.In some embodiments the cyclization is carried out in2-methyltetrahydrofuran. In some embodiments the cyclization comprisestreating a compound of Formula (IV) or a salt thereof, for example acompound of (IVa) or a salt thereof, with potassium tert-butoxide in2-methyltetrahydrofuran. In some embodiments the compound of Formula(III) or a salt thereof is further acidified and isolated byprecipitation with methylcyclohexane.

In some embodiments X of the compound of Formula (II) or a salt thereofin step d) is Cl, Br, or I. In some embodiments X of the compound ofFormula (II) or a salt thereof in step d) is Cl. In some embodiments thehalogenating comprises treating the compound of Formula (III) or a saltthereof with a halogenating agent. In some embodiments the halogenatingagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH);N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In someembodiments the halogenating agent is DCDMH and the compound of Formula(II) or a salt thereof is a compound of Formula (IIa) or a salt thereof.

In some embodiments the aromatizing in step e) is carried out in asuitable solvent and optionally with an additive reagent. In someembodiments the aromatizing in step e) is carried out in a suitablesolvent which is a polar aprotic solvent selected from the groupconsisting of dimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodimentsthe aromatizing in step e) is carried out in the presence of an additivereagent in a solvent selected from the group consisting of acetonitrile,toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methylisobutyl ketone. In some embodiments the aromatizing is carried out inacetonitrile in the presence of an additive reagent. In some embodimentsthe additive reagent is a quaternary ammonium salt. In some embodimentsthe quaternary ammonium salt is selected from the group consisting oftetrabutylammonium bromide, benzyltriethylammonium chloride,tetrabutylammonium chloride, tetraethylammonium chloride andtetramethylammonium chloride. In some embodiments the quaternaryammonium salt is tetraethylammonium chloride. In some embodiments thearomatizing is carried out in acetonitrile with tetraetylammoniumchloride.

In some embodiments R of step b) is methyl and X of step d) is chloro.

Some embodiments describe the compound of Formula (I) or a salt thereofwherein the compound of Formula (VI) or a salt thereof is prepared byany process described herein. Some embodiments describe the compound ofFormula (I) or a salt or solvate thereof wherein the compound of Formula(VI) or a salt thereof is prepared by a process comprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding a dialkyl malonic ester of the Formula        R₁O(O)C—CH₂—C(O)OR₂, wherein each of R₁ and R₂ is independently        C₁₋₄ alkyl, to the compound of Formula (VIII) or a salt thereof        to form a compound of Formula (VII) or a salt thereof

-   -   -   wherein each R₁ and R₂ are as defined for the dialkyl            malonic ester;

    -   iii. hydrolyzing the compound of Formula (VII) or a salt thereof        to form the compound of Formula (VI) or a salt thereof.

In some embodiments the condensing in step i. comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step i. comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol.

In some embodiments each of R¹ and R² in step ii. is ethyl. In someembodiments the dialkyl malonic ester in step ii. isdi-tert-butylmalonate or diethyl malonate. In some embodiments, theadding in step ii. comprises contacting the malonic ester with thecompound of Formula (VIII) or a salt thereof in the presence of lithiumbromide/triethylamine.

Compound of Formula (I) Prepared by Process B

Some embodiments herein describe a compound of Formula (I) or a salt orsolvate thereof

prepared by a process comprising:

-   -   a) decarboxylating a compound of Formula (VI) or a salt thereof

-   -   -   to form a compound of Formula (V) or a salt thereof

-   -   b) esterifying the compound of Formula (V) or a salt thereof to        form a compound of Formula (IVa) or a salt thereof

-   -   c) cyclizing the compound of Formula (IVa) or a salt thereof to        form a compound of Formula (III) or a salt thereof

-   -   d) halogenating the compound of Formula (III) or a salt thereof        to form a compound of Formula (IIa) or a salt thereof

and

-   -   e) aromatizing the compound of Formula (IIa) or a salt thereof        to form the compound of Formula (I) or a salt or solvate        thereof.

Some embodiments describe the compound of Formula (I) or a salt orsolvate thereof wherein the process further comprises isolating thecompound of Formula (III) or a salt thereof. Some embodiments describethe compound of Formula (I) or a salt or solvate thereof wherein theprocess comprises isolating the compound of Formula (IIa) or a saltthereof. Some embodiments describe the compound of Formula (I) or a saltor solvate thereof wherein the process further comprises purifying thecompound of Formula (I) obtained from step e). In some embodiments thepurifying comprises crystallization of Formula (I). In some embodimentsthe compound of Formula (I) is crystal form 1. In some embodiments thecompound of Formula (I) is an anhydrous crystal. In some embodiments thecompound of Formula (I) has an X-ray powder diffraction patternsubstantially as shown in FIG. 1. In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8,19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values±0.1° 2θ experimental error). In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with at least nine, or at least eight,or at least seven, or at least six, or at least five, or at least four,or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2,21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isan acetic acid solvate in crystalline solid state form. In someembodiments, the compound of Formula (I) is an acetic acid solvate incrystalline solid state form which has an X-ray powder diffractionpattern substantially as shown in FIG. 2. In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 20 values, ±0.1° 2θ experimental error). In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withat least six, or at least five, or at least four, or at least threespecific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).

In some embodiments the decarboxylating of the compound of Formula (VI)or a salt thereof in step a) comprises the presence of a base. In someembodiments the base is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base is trimethylamine.In some embodiments the decarboxylating comprises heating the compoundof Formula (VI) or a salt thereof in the presence of trimethylamine.

In some embodiments the esterifying of the compound of Formula (V) or asalt thereof in step b) is carried out using methanol and hydrochloricacid to obtain the compound of Formula (IVa). In some embodiments theesterifying comprises treating the compound of Formula (V) or a saltthereof with aqueous hydrochloric acid in methanol.

In some embodiments the cyclization in step c) comprises contacting thecompound of Formula (IVa) or salt thereof, with a base. In someembodiments the cyclization is performed using potassium tert-butoxide.In some embodiments the cyclization is carried out in2-methyltetrahydrofuran. In some embodiments the cyclization comprisestreating a compound of Formula (IVa) or a salt thereof with potassiumtert-butoxide in 2-methyltetrahydrofuran. In some embodiments thecompound of Formula (III) or a salt thereof is further acidified andisolated by precipitation with methylcyclohexane.

In some embodiments the halogenating in step d) comprises treating thecompound of Formula (III) or a salt thereof with a halogenating agent.In some embodiments the halogenating agent is selected from1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS);and trichloroisocyanuric acid (TCCA). In some embodiments thehalogenating agent is DCDMH.

In some embodiments the aromatizing in step e) is carried out in asuitable solvent and optionally with an additive reagent. In someembodiments the aromatizing in step e) is carried out in a suitablesolvent which is a polar aprotic solvent selected from the groupconsisting of dimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodimentsthe aromatizing in step e) is carried out in the presence of an additivereagent in a solvent selected from the group consisting of acetonitrile,toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methylisobutyl ketone. In some embodiments the aromatizing is carried out inacetonitrile in the presence of an additive reagent. In some embodimentsthe additive reagent is a quaternary ammonium salt. In some embodimentsthe quaternary ammonium salt is selected from the group consisting oftetrabutylammonium bromide, benzyltriethylammonium chloride,tetrabutylammonium chloride, tetraethylammonium chloride andtetramethylammonium chloride. In some embodiments the quaternaryammonium salt is tetraethylammonium chloride. In some embodiments thearomatizing is carried out in acetonitrile with tetraetylammoniumchloride.

Some embodiments describe the compound of Formula (I) or a salt thereofwherein the compound of Formula (VI) or a salt thereof is prepared byany process described herein. Some embodiments describe the compound ofFormula (I) or a salt thereof wherein the compound of Formula (VI) or asalt thereof is prepared by a process comprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding a diethyl malonic ester to the compound of        Formula (VIII) or a salt thereof to form a compound of Formula        (VIIa) or a salt thereof

and

-   -   iii. hydrolyzing the compound of Formula (VIIa) or a salt        thereof to form the compound of Formula (VI) or a salt thereof.

In some embodiments the condensing in step i. comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step i. comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol.

In some embodiments, the adding in step ii. comprises contacting thediethyl malonic ester with the compound of Formula (VIII) or a saltthereof in the presence of lithium bromide/triethylamine.

Compound of Formula (I) Prepared by Process C

Some embodiments describe a compound of Formula (I) or a salt or solvatethereof

prepared by a process comprising:

-   -   a) heating a compound of Formula (VI)

-   -   with catalytic triethylamine to form a compound of Formula (V)

-   -   b) heating the compound of Formula (V) with methanol and aqueous        hydrochloric acid to form a compound of Formula (IVa)

-   -   c) treating the compound of Formula (IVa) with potassium        tert-butoxide to form a compound of Formula (III)

-   -   d) chlorination the compound of Formula (III) with 1,        3-dichloro-5,5-dimethylhydantoin to form a compound of Formula        (IIa)

and

-   -   e) heating the compound of Formula (IIa) in acetonitrile with        tetraethylammonium chloride to form the compound of Formula (I)        or a salt or solvate thereof.

Some embodiments describe the compound of Formula (I) or a salt orsolvate thereof wherein the process further comprises isolating thecompound of Formula (III). Some embodiments describe the compound ofFormula (I) wherein the process comprises isolating the compound ofFormula (IIa). Some embodiments describe the compound of Formula (I) ora salt or solvate thereof wherein the process further comprisespurifying the compound of Formula (I) obtained from step e). In someembodiments the purifying comprises crystallization of Formula (I). Insome embodiments the compound of Formula (I) is crystal form 1. In someembodiments the compound of Formula (I) is an anhydrous crystal. In someembodiments the compound of Formula (I) has an X-ray powder diffractionpattern substantially as shown in FIG. 1. In some embodiments thecompound of Formula (I) is in a crystalline solid state characterised byan X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0,17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (allvalues ±0.1° 2θ experimental error). In some embodiments the compound ofFormula (I) is in a crystalline solid state characterised by an X-raypowder diffraction (XRPD) pattern with at least nine, or at least eight,or at least seven, or at least six, or at least five, or at least four,or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2,21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In some embodiments the compound of Formula (I) isan acetic acid solvate in crystalline solid state form. In someembodiments, the compound of Formula (I) is an acetic acid solvate incrystalline solid state form which has an X-ray powder diffractionpattern substantially as shown in FIG. 2. In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 2θ values, ±0.1° 2θ experimental error). In another embodiment thecompound of Formula (I) is an acetic acid solvate in crystalline solidstate characterised by an X-ray powder diffraction (XRPD) pattern withat least six, or at least five, or at least four, or at least threespecific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).

Some embodiments describe the compound of Formula (I) or a salt thereofwherein the compound of Formula (VI) or a salt thereof is prepared byany process described herein. Some embodiments describe the compound ofFormula (I) or a salt or solvate thereof wherein the compound of Formula(VI) is prepared by a process comprising:

-   -   i. treating methyl isobutyl ketone with trans-cinnamaldehyde in        the presence of methanolic sodium hydroxide to form a compound        of Formula (VIII)

-   -   ii. treating the compound of Formula (VIII) with diethyl        malonate in the presence of lithium bromide and triethylamine to        form a compound of Formula (VIIa)

-   -   iii. hydrolyzing the compound of Formula (VIIa) with sodium        hydroxide and ethanol to form the compound of Formula (VI).        Compound of Formula (VI) Prepared by a Process

Some embodiments herein describe a compound of Formula (VI) or a saltthereof

prepared by a process comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine.

Compound of Formula (V) Prepared by a Process

Some embodiments herein describe a compound of Formula (V) or a saltthereof

prepared by a process comprising decarboxylating a compound of Formula(VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. In some embodiments the base is selected from imidazole,pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments thebase is trimethylamine. In some embodiments the decarboxylatingcomprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine. In some embodiments the compound of Formula(VI) or a salt thereof is prepared by any process described herein. Someembodiments describe the compound of Formula (V) or a salt thereofwherein the compound of Formula (VI) or a salt thereof is prepared by aprocess comprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   iii. hydrolyzing the compound of Formula (VIIa) or a salt        thereof to form the compound of Formula (VI) or a salt thereof.

Some embodiments herein describe a compound of Formula (V) or a saltthereof

prepared by a process comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof

and

-   -   d) decarboxylating the compound of Formula (VI) or a salt        thereof, in the presence of a base, to form the compound of        Formula (V) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine. In some embodiments the basein step d) is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base in step d) istrimethylamine. In some embodiments the decarboxylating in step d)comprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine.

Compound of Formula (IVa) Prepared by a Process

Some embodiments herein describe a compound of Formula (IVa) or a saltthereof

prepared by a process comprising esterifying a compound of Formula (V)or a salt thereof

to form the compound of Formula (IVa) or a salt thereof. In someembodiments the esterifying of the compound of Formula (V) or a saltthereof is carried out using methanol and hydrochloric acid to obtaincompound (IVa) or a salt thereof. In some embodiments the esterifyingcomprises treating the compound of Formula (V) or a salt thereof withaqueous hydrochloric acid in methanol. Some embodiments describe thecompound of Formula (IVa) or a salt thereof wherein the compound ofFormula (V) or a salt thereof is prepared by any process describedherein. Some embodiments describe the compound of Formula (IVa) or asalt thereof wherein the compound of Formula (V) or a salt thereof isprepared by a process comprising decarboxylating a compound of Formula(VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. Some embodiments describe the compound of Formula (IVa) or asalt thereof wherein the compound of Formula (V) or a salt thereof isprepared by any process described herein. Some embodiments describe thecompound of Formula (IVa) or a salt thereof wherein the compound ofFormula (V) or a salt thereof is prepared by a process comprisingdecarboxylating a compound of Formula (VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. Some embodiments describe the compound of Formula (IVa) or asalt thereof wherein the compound of Formula (VI) or a salt thereof isprepared by any process described herein. Some embodiments describe thecompound of Formula (IVa) or a salt thereof wherein the compound ofFormula (VI) or a salt thereof is prepared by a process comprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   iii. hydrolyzing the compound of Formula (VIIa) or a salt        thereof to form the compound of Formula (VI) or a salt thereof.

Some embodiments herein describe a compound of Formula (IVa) or a saltthereof

prepared by a process comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof

-   -   d) decarboxylating the compound of Formula (VI) or a salt        thereof, in the presence of a base, to form the compound of        Formula (V) or a salt thereof

and

-   -   e) esterifying a compound of Formula (V) or a salt thereof to        form the compound of Formula (IVa) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine. In some embodiments the basein step d) is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base in step d) istrimethylamine. In some embodiments the decarboxylating in step d)comprises heating the compound of Formula or a salt thereof VI in thepresence of trimethylamine. In some embodiments the esterifying of thecompound of Formula (V) or a salt thereof in step e) is carried outusing methanol and hydrochloric acid to obtain compound (IVa). In someembodiments the esterifying in step e) comprises treating the compoundof Formula (V) or a salt thereof with aqueous hydrochloric acid inmethanol.

Compound of Formula (IIa) Prepared by a Process

Some embodiments herein describe a compound of Formula (IIa) or a saltthereof

prepared by a process comprising halogenating a compound of Formula(III) or a salt thereof

to form the compound of Formula (IIa) or a salt thereof. In someembodiments the halogenating comprises treating the compound of Formula(III) or a salt thereof with a halogenating agent. In some embodimentsthe halogenating agent is selected from1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS);and trichloroisocyanuric acid (TCCA). Some embodiments describe thecompound of Formula (IIa) or a salt thereof wherein the compound ofFormula (III) or a salt thereof is prepared by any process describedherein. Some embodiments describe the compound of Formula (IIa) or asalt thereof wherein the compound of Formula (III) or a salt thereof isprepared by a process comprising cyclizing a compound of Formula (IVa)or a salt thereof

to form the compound of Formula (III) or a salt thereof. Someembodiments describe the compound of Formula (IIa) or a salt thereofwherein the compound of Formula (IVa) or a salt thereof is prepared byany process described herein. Some embodiments describe the compound ofFormula (IIa) or a salt thereof wherein the compound of Formula (IVa) ora salt thereof is prepared by a process comprising esterifying acompound of Formula (V) or a salt thereof

Some embodiments describe the compound of Formula (IIa) or a saltthereof wherein the compound of Formula (V) or a salt thereof isprepared by any process described herein. Some embodiments describe thecompound of Formula (IIa) or a salt thereof wherein the compound ofcompound of Formula (V) or a salt thereof is prepared by a processcomprising decarboxylating a compound of Formula (VI) or a salt thereof

in the presence of a base, to form the compound of Formula (V) or a saltthereof. Some embodiments describe the compound of Formula (IIa) or asalt thereof wherein the compound of Formula (VI) or a salt thereof isprepared by any process described herein. Some embodiments describe thecompound of Formula (IIa) or a salt thereof wherein the compound ofFormula (VI) or a salt thereof is prepared by a process comprising:

-   -   i. condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   ii. adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

and

-   -   iii. hydrolyzing the compound of Formula (VIIa) or a salt        thereof to form the compound of Formula (VI) or a salt thereof.

Some embodiments herein describe a compound of Formula (IIa) or a saltthereof

prepared by a process comprising:

-   -   a) condensing trans-cinnamaldehyde or a salt thereof with methyl        isobutyl ketone to form a compound of Formula (VIII) or a salt        thereof

-   -   b) adding diethyl malonate to the compound of Formula (VIII) or        a salt thereof to form a compound of Formula (VIIa) or a salt        thereof

-   -   c) hydrolyzing the compound of Formula (VIIa) or a salt thereof        to form the compound of Formula (VI) or a salt thereof

-   -   d) decarboxylating the compound of Formula (VI) or a salt        thereof, in the presence of a base, to form the compound of        Formula (V) or a salt thereof

-   -   e) esterifying a compound of Formula (V) or a salt thereof to        form the compound of Formula (IVa) or a salt thereof

-   -   f) cyclizing a compound of Formula (IVa) or a salt thereof to        form the compound of Formula (III) or a salt thereof

and

-   -   g) halogenating the compound of Formula (III) or a salt thereof        to form the compound of Formula (IIa) or a salt thereof.

In some embodiments the condensing in step a) comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde or a salt thereofin the presence of lithium, potassium or sodium hydroxide, for examplethe condensation is performed using potassium or sodium hydroxide inmethanol. In some embodiments the condensing in step a) comprisestreating the methyl isobutyl ketone with the trans-cinnamaldehyde or asalt thereof in the presence of sodium hydroxide in methanol. In someembodiments, the adding in step b) comprises contacting the diethylmalonate with the compound of Formula (VIIIa) or a salt thereof in thepresence of lithium bromide/triethylamine. In some embodiments the basein step d) is selected from imidazole, pyridine, and lutidine(2,6-dimethylpyridine). In some embodiments the base in step d) istrimethylamine. In some embodiments the decarboxylating in step d)comprises heating the compound of Formula (VI) or a salt thereof in thepresence of trimethylamine. In some embodiments the esterifying of thecompound of Formula (V) or a salt thereof in step e) is carried outusing methanol and hydrochloric acid to obtain compound (IVa). In someembodiments the esterifying in step e) comprises treating the compoundof Formula (V) or a salt thereof with aqueous hydrochloric acid inmethanol. In some embodiments the halogenating in step g) comprisestreating the compound of Formula (III) or a salt thereof with ahalogenating agent. In some embodiments the halogenating agent isselected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH);N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In someembodiments the halogenating agent is DCDMH.

Compounds

Some embodiments describe a compound of Formula (I) in crystalline solidstate form (Form 1) which has an X-ray powder diffraction patternsubstantially as shown in FIG. 1. In some embodiments the compound ofFormula (I) in form 1 is characterised by an X-ray powder diffraction(XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5,22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θexperimental error). In another embodiment there the compound of Formula(I) in form 1 is characterised by an X-ray powder diffraction (XRPD)pattern with at least nine, or at least eight, or at least seven, or atleast six, or at least five, or at least four, or at least threespecific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3,24.5, 26.2 and 27.9 degrees (all values ±0.1° 2θ experimental error). Insome embodiments the compound of Formula (I) is at least 80% form 1. Insome embodiments the compound of Formula (I) is at least 85% form 1. Insome embodiments the compound of Formula (I) is at least 90% form 1. Insome embodiments the compound of Formula (I) is at least 95% form 1. Insome embodiments the compound of Formula (I) is at least 99% form 1. Insome embodiments the compound of Formula (I) is about 90%, about 91%,about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about98%, or about 99% form 1.

Some embodiments describe an acetic acid solvate of the compound ofFormula (I). In some embodiments, the acetic acid solvate of thecompound of Formula (I) is in crystalline solid state form which has anX-ray powder diffraction pattern substantially as shown in FIG. 2. Inanother embodiment the acetic acid solvate of the compound of Formula(I) is characterised by an X-ray powder diffraction (XRPD) pattern withspecific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees(all 20 values, ±0.1° 2θ experimental error). In another embodiment theacetic acid solvate of the compound of Formula (I) is characterised byan X-ray powder diffraction (XRPD) pattern with at least six, or atleast five, or at least four, or at least three specific peaks selectedfrom peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all2θ values, ±0.1° 2θ experimental error). In some embodiments thecompound of Formula (I) is at least 80% acetic acid solvate of Formula(I). In some embodiments the compound of Formula (I) is at least 85%acetic acid solvate of Formula (I). In some embodiments the compound ofFormula (I) is at least 90% acetic acid solvate of Formula (I). In someembodiments the compound of Formula (I) is at least 95% acetic acidsolvate of Formula (I). In some embodiments the compound of Formula (I)is at least 99% acetic acid solvate of Formula (I). In some embodimentsthe compound of Formula (I) is about 90%, about 91%, about 92%, about93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%acetic acid solvate of Formula (I).

It will be understood by one of skill in the art that the percentage ofa particular form of a compound of Formula (I) is expressed in relationto all forms of Formula (I) present in a sample. For example the phrase“the compound of Formula (I) is at least 95% form 1” is meant to conveythat at least 95% of all forms of the compound of Formula (I) present isin form 1. Similarly, the phrase “the compound of Formula (I) is atleast 80% acetic acid solvate of Formula (I)” means that at least 80% ofa sample of the compound of Formula (I) is in the form of an acetic acidsolvate.

Some embodiments describe a compound of Formula (IIa) or a salt thereof

Some embodiments describe a compound of Formula (IVa) or a salt thereof

Some embodiments describe a compound of Formula (V) or a salt thereof

Some embodiments describe a compound of Formula (VI) or a salt thereof

Pharmaceutical Compositions

Embodiments herein describe a pharmaceutical composition comprising acompound of Formula (I) or a salt or solvate thereof prepared accordingto any embodiment described herein and a pharmaceutically acceptableexcipient.

Some embodiments describe pharmaceutical composition comprising atherapeutically effective amount of compound of Formula (I) of form 1and a pharmaceutically acceptable excipient. In some embodiments thecomposition of Formula (I) of form 1 is characterised by an X-ray powderdiffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1,20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees 2θ (±0.1° 2θ). Insome embodiments the compound of Formula (I) of form 1 is characterisedby an X-ray powder diffraction (XRPD) pattern with at least nine, or atleast eight, or at least seven, or at least six, or at least five, or atleast four, or at least three specific peaks selected from 15.0, 17.8,19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees degrees 2θ(±0.1° 2θ). In some embodiments the compound of Formula (I) is at least80% form 1. In some embodiments the compound of Formula (I) is at least85% form 1. In some embodiments the compound of Formula (I) is at least90% form 1. In some embodiments the compound of Formula (I) is at least95% form 1. In some embodiments the compound of Formula (I) is at least99% form 1. In some embodiments the compound of Formula (I) is about90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,about 97%, about 98%, or about 99% form 1.

Some embodiments describe a pharmaceutical composition comprising atherapeutically effective amount of an acetic acid solvate of thecompound of Formula (I) and a pharmaceutically acceptable excipient. Insome embodiments, the acetic acid solvate of the compound of Formula (I)is in a crystalline solid state form which has an X-ray powderdiffraction with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2,and 24.8 degrees 2θ (±0.1° 2θ). In some embodiments the acetic acidsolvate of a compound of Formula (I) is characterised by an X-ray powderdiffraction (XRPD) pattern with at least six, or at least five, or atleast four, or at least three specific peaks selected from peaks at 6.7,10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (±0.1° 2θ). In someembodiments the compound of Formula (I) is at least 80% acetic acidsolvate of Formula (I). In some embodiments the compound of Formula (I)is at least 85% acetic acid solvate of Formula (I). In some embodimentsthe compound of Formula (I) is at least 90% acetic acid solvate ofFormula (I). In some embodiments the compound of Formula (I) is at least95% acetic acid solvate of Formula (I). In some embodiments the compoundof Formula (I) is at least 99% acetic acid solvate of Formula (I). Insome embodiments the compound of Formula (I) is about 90%, about 91%,about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about98%, or about 99% acetic acid solvate of Formula (I).

Some embodiments describe a pharmaceutical composition comprising acompound of Formula (IIa) and a pharmaceutically acceptable excipient.

Some embodiments describe a pharmaceutical composition comprising acompound of Formula (IVa) and a pharmaceutically acceptable excipient.

Some embodiments describe a pharmaceutical composition comprising acompound of Formula (V) and a pharmaceutically acceptable excipient.

Some embodiments describe a pharmaceutical composition comprising acompound of Formula (VI) and a pharmaceutically acceptable excipient.

In any of the foregoing pharmaceutical compositions, the compound ofFormula (I) is present in a therapeutically effective amount.

Methods of preparing pharmaceutical compositions of the compound ofFormula (I) and salts and solvates thereof are familiar to those skilledin the art, which are described in Remington: The Science and Practiceof Pharmacy, 21^(st) Edition 2006.

In some embodiments, a compound of Formula (I) or a salt or solvatethereof prepared by any process described herein, is at least 80% pureby weight. In some embodiments, a compound of Formula (I) or a salt orsolvate thereof prepared by any process described herein, is at least85% pure by weight. In some embodiments, a compound of Formula (I) or asalt or solvate thereof prepared by any process described herein, is atleast 90% pure by weight. In some embodiments, a compound of Formula (I)or a salt or solvate thereof prepared by any process described herein,is at least 95% pure by weight. In some embodiments, a compound ofFormula (I) or a salt or solvate thereof prepared by any processdescribed herein, is at least 99% pure by weight. In some embodiments, acompound of Formula (I) or a salt or solvate thereof prepared by anyprocess described herein, is about 90%, about 91%, about 92%, about 93%,about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%,pure by weight.

Definitions

The term “C₁₋₄ alkyl” means a straight or branched alkyl containing atleast one, and at most four, carbon atoms. Examples of “C₁₋₄ alkyl” asused herein include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, isobutyl, isopropyl and t-butyl.

References herein to compounds of specified Formulae and “salts thereof”cover the compounds as free bases, or as salts thereof, for example aspharmaceutically acceptable salts thereof. For a review of suitablepharmaceutically acceptable salts see Berge et al., J. Pharm. Sci.,66:1-19, (1977).

“Solvates” of the compounds of the specified Formulae may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve non-aqueous solvents suchas ethanol, iso-propyl alcohol, N,N-dimethylsulfoxide (DMSO), aceticacid, ethanolamine, and ethyl acetate, or they may involve water as thesolvent that is incorporated into the crystalline lattice.

As used herein a “pharmaceutically acceptable excipient” refers to oneor more pharmaceutically acceptable material, composition or vehicleinvolved in giving form or consistency to the pharmaceuticalcomposition. Each excipient must be compatible with the otheringredients of the pharmaceutical composition when commingled such thatinteractions which would substantially reduce the efficacy of thecompound of Formula (I) or a pharmaceutically acceptable salt thereofwhen administered to a patient.

As used herein an X-ray powder diffraction pattern that is“substantially as shown in FIG. 1” or “substantially as shown in FIG. 2”relates to an X-ray powder diffraction pattern that would be consideredby one skilled in the art to represent a compound possessing the samecrystal form as the compound that provided the XRPD pattern of FIG. 1 orFIG. 2. It is well known and understood to those skilled in the art thatthe apparatus employed, humidity, temperature, orientation of the powdercrystals, and other parameters involved in obtaining an X-ray powderdiffraction pattern may cause some variability in the appearance,intensities, and positions of the lines in the diffraction pattern. Thusan X-ray powder diffraction pattern that is “substantially as shown inFIG. 1” or “substantially as shown in FIG. 2” may not necessarily showeach of the lines of any one of the diffraction patterns presentedherein, and/or may show a slight change in appearance, intensity, or ashift in position of said lines resulting from differences in theconditions involved in obtaining the data. A person skilled in the artis capable of determining (e.g. by overlaying) if a sample of acrystalline compound has the same form as, or a different form from, aform disclosed herein by comparison of their XRPD patterns.

Throughout the description and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

A “therapeutically effective amount” of a compound, pharmaceuticallyacceptable salt or solvate thereof or pharmaceutical compositionaccording to any embodiment described herein, is an amount sufficient toproduce a selected effect on at least one symptom or parameter of aspecific disease or disorder. The therapeutic effect may be objective(i.e., measurable by some test or marker) or subjective (i.e., subjectgives an indication of or feels an effect or physician observes achange). The effect contemplated herein, includes both medicaltherapeutic and/or prophylactic treatment, as appropriate. The specificdose of a compound administered according to this disclosure to obtaintherapeutic and/or prophylactic effects is determined by the particularcircumstances surrounding the case, including, for example, the compoundadministered, the route of administration, the co-administration ofother active ingredients, the condition being treated, the activity ofthe specific compound employed, the specific composition employed, theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed and the duration of the treatment. Thetherapeutically effective amount administered will be determined by thephysician in the light of the foregoing relevant circumstances and theexercise of sound medical judgment. A therapeutically effective amountof a compound, according to any embodiment described herein, istypically an amount such that when it is administered in aphysiologically tolerable excipient composition, it is sufficient toachieve an effective systemic concentration or local concentration inthe tissue.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore, the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification. Various embodiments of the presentinvention will be illustrated with reference to the followingnon-limiting examples. The following examples are for illustrativepurposes only and are not to be construed as limiting the invention inany manner.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Unless otherwise noted,all starting materials were obtained from commercial suppliers and usedwithout further purification. Specifically, the following abbreviationsmay be used in the examples and throughout the specification:

ABBREVIATIONS AcOH acetic acid APCI Atmospheric Pressure ChemicalIonization aq aqueous CH₃CN acetonitrile CH₃COOH acetic acid CH₃OHmethanol DCDMH 1,3-dichloro-5,5-dimethylhydantoin DMAC dimethylacetamideDMF N,N-dimethylformamide DMPU 1,3-dimethyltetrahydropyrimidin-2(1H)-oneDMSO dimethyl sulfoxide Et ethyl EtOH ethanol equiv equivalents HC1hydrochloric acid HRMS High Resolution Mass Spectrometry iPr isopropylKOH potassium hydroxide KOtButoxide potassium tert-butoxide LiBr lithiumbromide Me methyl 2-MeTHF 2-methyl tetrahydrofuran MHz megahertz MIBKmethyl isobutyl ketone MS mass spectrometry NaOH sodium hydroxide NEt₃triethylamine NH₄Cl ammonium chloride NMR Nuclear Magnetic ResonanceTBAC tetrabutylammonium chloride TBME tert-butyl methyl ether tButert-butyl tBuOK potassium tert-butoxide TCCA trichloroisocyanuric acidTEAC tetraethylammonium chloride

EXAMPLES

General Experimental Procedures. All reactions were performed underpositive pressure of nitrogen in a Jacketed Laboratory Reactor equippedwith overhead stirring and fitted with Teflon septa.

Materials: Commercial solvents and reagents were used as received.

Instrumentation:

Unless otherwise stated proton nuclear magnetic resonance spectra (¹HNMR) were recorded at 400 MHz at 25° C. Chemical shifts are expressed inparts per million (ppm, δ scale) downfield from tetramethylsilane andare referenced to residual proton in the NMR solvent. Data arerepresented as follows: chemical shift, multiplicity (s=singlet,d=doublet, sep=septet, m=multiplet and/or multiple resonances,br=broad), integration, coupling constant in Hertz, and assignment.Proton-decoupled carbon nuclear magnetic resonance spectra (¹³C NMR)were recorded at 100 MHz at 25° C. Chemical shifts are expressed inparts per million (ppm, δ scale) downfield from tetramethylsilane andare referenced to the carbon resonances of the solvent. High-resolutionmass spectrometry (HRMS) were obtained using an Orbitrap mass analyzer.

The X-ray powder diffraction (XRPD) data were acquired on a PANalyticalX'Pert Pro powder diffractometer, model PW3050/60, using an X'Celeratordetector. The acquisition conditions were: radiation: Cu Kα, generatortension: 45 kV, generator current: 40 mA, step size: 0.017° 2θ, time perstep: 500 seconds, divergence slit type: fixed, divergence slit size:0.4354°, measurement temperature: 20-25° C., goniometer radius: 240 mm.The sample was prepared by packing sample in a 0.9 mm capillary, or zerobackground silicone sample holder. Peak positions were obtained usingPANalytical X'Pert Highscore Plus software. The margin of error isapproximately ±0.1° 2θ for each of the peak assignments.

Example 1 Synthesis of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one,(compound of Formula (VIII))

A solution of sodium hydroxide (11.4 g, 284 mmol, 1.5 equiv) in methanol(100 mL) was added dropwise over 1 hour to a stirred solution ofcinnamaldehyde (compound of Formula (IX)) (25 g, 189 mmol, 1 equiv) andmethyl isobutyl ketone (75 mL, 602 mmol, 3.2 equiv) at −5° C. Uponcompletion of the addition, the reaction mixture was stirred for 2 hoursat 0° C. Toluene (250 mL) and water (125 mL) were then added directly tothe reactor at 0° C. and the stirring biphasic mixture allowed to warmto 20° C. The aqueous layer was removed and the organic layer was washedwith water (2×75 mL). The washed organic layer was then dried viaazeotropic distillation under vacuum to a final solution volume of 75 mLor until analysis via Karl Fischer titration revealed water content lessthan 0.2%. The crude material was utilized in the next transformationwithout any further processing.

Example 2 Synthesis of (E)-di-tert-butyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate, (Compound of FormulaVII in which R₁+R₂=tBu)

The concentrated solution obtained in the previous step (example 1) wasdiluted with toluene such that the total volume of the solution was 175mL. To the solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one,(compound of Formula (VIII)) in toluene at 20° C. was then addeddi-tert-butyl malonate (40.3 mL, 180 mmol, 0.95 equiv), triethylamine(13.1 mL, 94.5 mmol, 0.5 equiv), and powdered lithium bromide (3.28 g,37.8 mmol, 0.2 equiv). The heterogeneous reaction mixture was stirredfor 2 hours at 20° C. Water (200 mL) was then charged directly to thestirring reaction mixture. The layers were allowed to separate and theaqueous layer discarded. The resulting product solution was utilized inthe next transformation without any further processing. Alternatively,the di-tert-butyl malonate addition product (E)-di-tert-butyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of Formula(VII)) could also be isolated via concentration of the toluene solutionand crystallization from isopropyl alcohol/water (3:2) to provide(E)-di-tert-butyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate(compound of Formula (VII)) as a light yellow solid.

¹H NMR (400 MHz, DMSO) δ 7.32-7.29 (m, 4H), 7.24-7.18 (m, 1H), 6.38 (d,1H, J=16 Hz), 6.12 (dd, 1H, J=16, 8.4 Hz), 3.39 (d, 1H, J=8.4 Hz),3.27-3.20 (m, 1H), 2.70 (dd, 1H, J=16.8, 9.2 Hz), 2.58 (dd, 1H, J=16.8,4.4 Hz), 2.28 (d, 2H, J=7.2 Hz), 1.98 (sep, 1H, J=6.8 Hz), 1.39 (s, 9H),1.33 (S, 9H), 0.81 (d, 3H, J=6.4 Hz), 0.80 (d, 3H, J=6.4 Hz).

¹³C NMR (100 MHz, DMSO) δ 208.2 (C), 167.0 (C), 166.8 (C), 136.7 (C),131.2 (CH), 129.1 (CH), 128.6 (CH), 127.3 (CH), 125.9 (CH), 81.2 (C),80.9 (C), 56.8 (CH), 51.4 (CH₂), 45.0 (CH₂), 37.7 (CH), 27.5 (CH₃), 27.4(CH₃), 23.9 (CH), 22.3 (CH₃), 22.2 (CH₃).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₂₆H₃₉O₅, 431.2792; found, 431.2754.

Example 3 Synthesis of (E)-diethyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate, (Compound of FormulaVIIa)

A concentrated solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one(about 7.6 moles) is diluted with toluene. To the solution of(5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one, (compound of Formula(VIII)) in toluene at 20° C. is then added diethyl malonate (1.83 kg,1.73 L, 1.5 equiv), triethylamine (1.15 kg, 1.58 L, 1.5 equiv), andpowdered lithium bromide (131 g, 0.2 equiv). The heterogeneous reactionmixture is stirred at 35-40° C. for at least 8 hours. Water (8 L, 8vols) is then charged directly to the stirring reaction mixture andstirred at 35° C. for 15-30 minutes. The layers are allowed to separateand the aqueous layer discarded. The resulting product solution isutilized in the next transformation without any further processing.Alternatively, the diethyl malonate addition product (E)-diethyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of Formula(VIIa)) can also be isolated via concentration of the toluene solutionand crystallization to provide (E)-diethyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of Formula(VIIa)).

¹H NMR (700 MHz, DMSO) δ 7.30 (m, 2H), 7.30 (m, SH0, 7.21 (m, 1H), 6.39(d, 1H) J=15.8 Hz), 6.14 (dd, 1H, J=15.99 Hz, J=8.9 Hz), 4.12 (q, 2H,J=7.13 Hz), 4.06 (m, 2H), 3.68 (d, 1H, J=8.1 Hz), 3.33 (m, 1H), 2.73(dd, 1H, J=16.9 Hz, J=9.0 Hz), 2.63 (m, 1H,), 2.28 (d, 2H, 6.9 Hz), 1.98(m, 1H, 6.7 Hz), 1.16 (t, 3H, J=7.1 Hz), 1.10 (t, 3H, J=7.0 Hz), 0.81(d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.7 Hz).

¹³C NMR (176 MHz, DMSO) δ 208.1 (C), 167.7 (C), 167.6 (C), 136.6 (C),131.4 (CH), 128.9 (CH), 127.4 (CH), 125.9 (CH), 61.0 (CH2), 60.8 (CH2),55.0 (CH), 51.3 (CH2), 44.8 (CH2), 37.7 (CH), 23.8 (CH), 22.3 (CH3),22.2 (CH3), 13.9 (CH3), 13.9 (CH3).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₂₂H₃₁O₅, 375.2166; found, 375.2158.

Example 4 Synthesis of(E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid, (Compound ofFormula (VI))

Method A

The toluene solution of (E)-di-tert-butyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of Formula(VII)) obtained in the previous step was diluted with acetic acid (50mL) and added drop wise over 1 hour to a stirred solution consisting ofacetic acid (100 mL) and concentrated aqueous hydrochloric acid (75 mL)at 60° C. Upon completion of the addition, the resulting solution wasstirred for 4 hours at 60° C. The product mixture was allowed to coolover 30 minutes to 20° C. and water (200 mL) added. The two layers werestirred vigorously at 20° C. and then allowed to settle. The aqueouslayer was then discarded and the toluene layer concentrated to dryness.To the resulting oil was added toluene (250 mL) and the solution heatedto 60° C. with stirring. The warm toluene solution was then allowed tocool slowly over 1 hour to 20° C. at which point(E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound ofFormula (VI)) precipitated from solution. The solid was then filteredand the wet cake washed with toluene (100 mL). The wet cake was thendried under vacuum at 30° C. for 12 hours to afford(E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound ofFormula (VI)) as a white crystalline solid (37.3 g, 62% fromcinnamaldehyde (compound of Formula (IX)).

Method B

A toluene solution of (E)-diethyl2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate from example 3(about7.6 moles, compound of Formula (VIIa)) at 20-30° C. was charged with 6Maqueous sodium hydroxide (5.05 L, 4 equiv), toluene (0.5 L or 0.5 vols),and 200 proof ethanol (2 vols) and the contents were stirred for atleast 4 h at T_(J)=20° C. Once complete, the temperature was adjusted to35-50° C. and after stirring for at least 30 minutes agitation wasstopped and the layers were separated. The aqueous layer was cooled to0-5° C. and the pH was adjusted with conc. HCl to a pH of 0-1 (required2.9 L or 4.7 equiv), while maintaining the temperature at 10° C. or lessduring the addition. Once the desired pH was reached the vessel wascharged with TBME (3 L, 3 vols) and the biphasic mixture was warmed to20-25° C. The mixture was stirred for 15-30 minutes and the layers wereseparated. To the organic layer was added toluene (7 L, 7 vols) andwater (6 L, 6 vols) and the mixture was stirred for 15-30 minutes. Thelayers were separated and toluene was added to achieve a fill of 16-18vols (3 L, 3 vols). The mixture was distilled down to about 9-9.5 volsusing vacuum distillation, the temperature was adjusted to 40-45° C. andthe mixture was seeded with 5 g of compound VI (0.2% w/w againsttheoretical yield). The mixture was stirred at 40-45° C. for 30-60minutes. Once nucleation was observed the mixture was diluted to 12volumes with toluene and held at 40-45° C. for at least 1 hour. Theslurry was cooled to 10-20° C. at 0.5° C./min and held at 10-20° C. forat least 1 hour. The solid was isolated by filtration and the filtercake was washed with toluene (2×7 vols). The solid was dried at 25-35°C. overnight in a vacuum oven to afford(E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound ofFormula (VI))

¹H NMR (400 MHz, DMSO) δ 12.78 (br s, 2H), 7.32-7.27 (m, 4H), 7.23-7.19(m, 1H), 6.39 (d, 1H, J=16 Hz), 6.17 (dd, 1H, J=16, 8.4 Hz), 3.43 (d,1H, J=8.4 Hz), 3.31-3.24 (m, 1H), 2.72 (dd, 1H, J=16.8, 8.8 Hz), 2.63(dd, 1H, J=16.4, 4 Hz), 2.28 (d, 2H, J=7.2 Hz), 1.98 (sep, 1H, J=6.8Hz), 0.81 (d, 3H, J=6.4 Hz), 0.80 (d, 3H, J=6.4 Hz).

¹³C NMR (100 MHz, DMSO) δ 208.4 (C), 169.6 (C), 169.5 (C), 136.8 (C),130.9 (CH), 129.6 (CH), 128.5 (CH), 127.3 (CH), 126.0 (CH), 55.7 (CH),51.4 (CH₂), 45.1 (CH₂), 37.6 (CH), 23.9 (CH), 22.3 (CH₃), 22.2 (CH₃).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₁₈H₂₃O₅, 319.1540; found, 319.1528.

Example 5 Synthesis of (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione,(Compound of Formula (III))

Triethylamine (4.4 mL, 31.4 mmol, 0.25 equiv) was charged to a stirredslurry of (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid(compound of Formula (VI)) (40.0 g, 126 mmol, 1 equiv) in toluene (210mL). The resulting mixture was heated to 110° C. and allowed to stir 2hours. The reaction mixture containing the non-isolated intermediate(E)-7-methyl-5-oxo-3-styryloctanoic acid (compound of Formula V) wasthen allowed to cool to 20° C. and charged with methanol (120 mL) andconcentrated aqueous hydrochloric acid (10.5 mL). The resulting solutionwas stirred for 4 hours at 60° C. The resulting mixture, containing thenon-isolated intermediate (E)-methyl 7-methyl-5-oxo-3-styryloctanoate(compound of Formula (IVa)), was allowed to cool to 20° C. and washedwith water (200 mL). The washed organic layer was then dried via vacuumdistillation to a final solution volume of 120 mL. The solution of themethyl ester (E)-methyl 7-methyl-5-oxo-3-styryloctanoate (compound ofFormula IVa) was then cooled to 0° C. A solution of potassiumtert-butoxide (19.7 g, 176 mmol, 1.4 equiv) in 2-methyltetrahydrofuran(80 mL) was then added drop wise over 1 hour to the cooled solution of(E)-methyl 7-methyl-5-oxo-3-styryloctanoate (compound of Formula (IVa)).Upon completion of the addition, the reaction mixture was warmed over 30minutes to 20° C. The warmed solution was stirred 1 hour at 20° C. Theresulting product mixture was then charged with 1.0 M aqueoushydrochloric acid (180 mL) and the biphasic mixture stirred 10 minutes.The aqueous layer was then discarded and the organic layer washed with10% aqueous sodium chloride (2×160 mL). To the solution of the(E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of Formula(III)) was then added methylcyclohexane (400 mL) drop wise over 1 hourat which point the product began to precipitate out. The slurry was thenfiltered and the wet cake washed with methylcyclohexane (120 mL). Thewet cake was then dried under vacuum at 30° C. for 12 hours to provide(E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of Formula(III)) as a white crystalline solid (25.3 g, 79% from(E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid, (compound ofFormula (VI)).

¹H NMR (400 MHz, DMSO) δ 10.33 (br s, 1H, OH), 7.39-7.37 (m, 2H),7.34-7.29 (m, 2H), 7.24-7.20 (m, 1H), 6.43 (d, 1H, J=16 Hz), 6.27 (dd,1H, J=16, 7.2 Hz), 3.08 (sep, 1H, J=7.2 Hz), 2.87-2.78 (m, 1H), 2.40(br, 4H), 1.08 (d, 6H, J=7.2 Hz).

¹³C NMR (100 MHz, DMSO) δ 136.8 (C), 132.5 (CH), 128.9 (CH), 128.6 (CH),127.3 (CH), 126.0 (CH), 119.2 (C), 36.1 (CH), 22.6 (CH), 20.4 (CH₃),other carbons undergo enol tautomerization.

HRMS-APCI (m/z) [M+H]⁺ calcd for C₁₇H₂₁O₂, 257.1536; found, 257.1519.

Example 6 Synthesis of(E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione, (Compound ofFormula (IIa))

A 1-L jacketed laboratory reactor was charged with(E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of Formula(III)) (55 g, 215 mmol, 1 equiv) and methanol (495 mL) resulting in aheterogeneous suspension. The mixture was heated to an internaltemperature of ˜45-50° C. at which point a homogeneous solution wasachieved. To this solution was charged solid1,3-dichloro-5,5-dimethylhydantoin (23.3 g, 118 mmol, 0.55 equiv)sequentially, in five equal portions. The product solution was thencooled to 40° C. over 10 minutes and seeded with 146 mg of(E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound ofFormula (IIa)). The mixture was aged for 30 minutes then cooled to 23°C. over 60 minutes. Water (330 mL) was then added drop wise to theslurry over 1 hour and the mixture stirred 30 minutes at 20° C. Theslurry was then filtered and the wet cake washed with 1:1 methanol/water(2×110 mL). The wet cake was then dried under vacuum at 45° C. for 12hours to provide (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione(compound of Formula (IIa)) as a white crystalline solid existing as a˜2:1 mixture of diastereomers (60.0 grams, 96%).

Isomer 1:

¹H NMR (400 MHz, DMSO) δ 7.41-7.39 (m, 2H), 7.36-7.32 (m, 2H), 7.23-7.22(m, 1H), 6.54 (d, 1H, J=16 Hz), 6.32 (dd, 1H, J=16, 7.2 Hz), 3.20-3.14(m, 3H), 2.84-2.77 (m, 1H), 2.73-2.72 (m, 1H), 2.70-2.69 (m, 1H), 0.82(d, 6H, J=6.8 Hz).

¹³C NMR (100 MHz, DMSO) δ 198.5 (C), 136.5 (C), 130.4 (CH), 129.9 (CH),128.6 (CH), 127.5 (CH), 126.1 (CH), 94.6 (C), 43.4 (CH₂), 35.0 (CH),32.8 (CH), 16.7 (CH₃).

Isomer 2:

¹H NMR (400 MHz, DMSO) δ 7.33-7.28 (m, 4H), 7.25-7.21 (m, 2H), 6.35 (dd,1H, J=16, 2 Hz), 6.03 (dd, 1H, J=16, 5.6 Hz), 3.48 (dd, 1H, J=14.8, 6Hz), 3.24-3.18 (m, 1H), 3.10 (sep, 1H, J=6.4 Hz), 2.86 (dd, 1H, J=14.8,3.6 Hz), 0.83 (d, 6H, J=6.4 Hz).

¹³C NMR (100 MHz, DMSO) δ 199.6 (C), 136.1 (C), 130.3 (CH), 130.1 (CH),128.6 (CH), 127.7 (CH), 126.1 (CH), 94.5 (C), 42.2 (CH₂), 34.7 (CH),30.9 (CH), 16.9 (CH₃).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₁₇H₂₀ClO₂, 291.1146; found, 291.1132.

Example 7 Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol,(compound of Formula (I))

A jacketed laboratory reactor was charged with(E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound ofFormula (IIa)) (407 g, 1.4 mol, 1 equiv), tetraethylammonium chloride(464 g, 2.8 mol, 2 equiv), and acetonitrile (1.2 L). The mixture washeated to 75-80° C. for 6 hours. The product mixture was then cooledover 30 minutes to 20° C. and diluted with tert-butyl methyl ether (3.26L). The resulting solution was washed four times with water (2 L eachwash). The resulting solution was concentrated to a volume of ˜610 ml.Acetic acid (815 ml) was charged and the solution was concentrated underreduced pressure to a volume of ˜1.3 L. The resultant slurry was heatedto 55° C. until homogeneous then cooled slowly to 35° C. over the courseof 1 hour during which time product precipitation commenced.Methylcyclohexane (6.5 L) was added to the slurry over the course of 2hours. Once the addition was complete, the mixture was further cooled to˜23° C. over one hour. The solids were filtered and washed twice with6:1 methylcyclohexane/AcOH. The isolated solid was then dried undervacuum at 80° C. for 24 hours to provide(E)-2-isopropyl-5-styrylbenzene-1,3-diol (compound of Formula (I)) as awhite crystalline solid (305 g, 86%).

¹H NMR (400 MHz, DMSO) δ 9.05 (s, 2H, OH), 7.58-7.55 (m, 2H), 7.37-7.33(m, 2H), 7.27-7.22 (m, 1H), 7.00 (d, 1H, J=16.4 Hz), 6.87 (d, 1H, J=16.4Hz), 6.47 (s, 2H), 3.43 (sep, 1H, J=7.2 Hz), 1.24 (d, 6H, J=7.2 Hz).

¹³C NMR (100 MHz, DMSO) δ 156.4 (C), 137.0 (C), 134.7 (C), 128.9 (CH),128.7 (CH), 127.4 (CH), 126.7 (CH), 126.3 (CH), 120.1 (C), 105.1 (CH),23.7 (CH), 20.6 (CH₃).

HRMS-APCI (m/z) [M+H]⁺ calcd for C₁₇H₁₉O₂, 255.1380; found, 255.1376.

The invention claimed is:
 1. A process for preparing a compound ofFormula (I) or a salt or solvate thereof

comprising aromatizing a compound of Formula (II)

wherein X is Cl, Br, or I to obtain the compound of Formula (I).
 2. Theprocess of claim 1 wherein X is Cl.
 3. The process of claim 1 whereinthe aromatizing comprises contacting the compound of Formula (II) withquaternary ammonium salt in a solvent.
 4. The process of claim 3,wherein the quaternary ammonium salt is tetraethylammonium chloride. 5.The process of claim 1, further comprising halogenating a compound ofFormula (III),

with a halogenating agent to obtain the compound of Formula (II).
 6. Theprocess of claim 5 wherein the halogenating agent is selected from thegroup consisting of 1,3-dichloro-5,5-dimethylhydantoin;N-chlorosuccinimide; and trichloroisocyanuric acid.
 7. The process ofclaim 5, wherein the halogenating is carried out in methanol and thehalogenating agent is 1,3-dichloro-5,5-dimethylhydantoin.
 8. The processof claim 5, further comprising cyclizing a compound of Formula (IV),

wherein R is C₁₋₄ alkyl, to obtain the compound of Formula (III).
 9. Theprocess of claim 8, wherein R is selected from the group consisting ofmethyl, ethyl, propyl, or butyl.
 10. The process of claim 8, wherein Ris methyl or t-butyl.
 11. The process of claim 8, wherein the cyclizingcomprises contacting the compound of Formula (IV) with potassiumtert-butoxide in 2-methyltetrahydrofuran.
 12. The process of claim 8,further comprising esterifying a compound of Formula (V) or a saltthereof

to obtain the compound of Formula (IV).
 13. The process of claim 12,wherein the esterifying comprises heating the compound of Formula (V) ora salt thereof with aqueous hydrochloric acid in methanol.
 14. Theprocess of claim 12, further comprising decarboxylating a compound ofFormula (VI)

in the presence of a base, to obtain the compound of Formula (V) or asalt thereof.
 15. The process of claim 14, wherein the decarboxylatingcomprises heating the compound of Formula (VI) in the presence oftriethylamine.
 16. The process of claim 14, further comprisinghydrolyzing a compound of Formula (VII)

wherein each of R¹ and R² is independently C₁₋₄ alkyl; to obtain thecompound of Formula (VI).
 17. The process of claim 16, wherein each ofR¹ and R² is ethyl.
 18. The process of claim 16, wherein the hydrolyzingcomprises treating the compound of Formula (VII) with sodium hydroxidein ethanol.
 19. The process of claim 16, further comprising adding adialkyl malonic ester to a compound of Formula (VIII)

to obtain the compound of Formula (VII).
 20. The process of claim 19wherein the dialkyl malonic ester is di-tert-butylmalonate or diethylmalonate.
 21. The process of claim 19, wherein the adding comprisescontacting the dialkyl malonic ester with the compound of Formula (VIII)in the presence of lithium bromide/triethylamine.
 22. The process ofclaim 19, further comprising condensing trans-cinnamaldehyde (IX)

with methyl isobutyl ketone to form the compound of Formula (VIII). 23.The process of claim 22, wherein the condensing comprises treating themethyl isobutyl ketone with the trans-cinnamaldehyde in the presence ofsodium hydroxide in methanol.